DESCRIPTION: (Applicant's Abstract) Opioids are fundamental in the pathogenesis of AIDS. The progression to AIDS dementia in HlV-1-positive individuals may be more rapid in opiate drug abusers than those abstaining from opiates. Brain regions with a high number/density of opioid receptors, such as the striatum and hippocampus, display increased viral loads and are preferentially susceptible to HIV infection. Although HIV itself propagates in microglia and astroglia, HIV-1 protein ' aboutvirotoxins," including gp120 and Tat, are subsequently released and cause the degeneration of neighboring neurons and glia. Despite evidence of an enhanced vulnerability of neurons and glia to HIV following opiate exposure, the reasons for the susceptibility are not understood. Our laboratory and others discovered that phenotypically distinct subsets of astroglia and microglia express about, 6, and/or K opioid receptors, and chronic exposure to opiate drugs of abuse destabiiize ion homeostasis and increase oxidative stress in neurons and glia similarly to HIV proteins. Our preliminary data indicate that opiates exacerbate the toxicity to HIV virotoxin-exposed striatal neurons. We predict the preferential susceptibi,'ity of HIV-1 afflicted individuals to opiates may result from the selective vulnerability of opioid receptor-expressing neurons and astroglia. Ourhypothesis is that opiates exacerbate HIV-1 toxicityin neurons and glia by fuffher stressing already jeoparclized [Ca2+]; and free radical homeostatic systems. To test this hypothesis, aim 1 will systematically assess the interactive role of ,u, 6, and K receptor activation on gp120/Tat-induced toxicity in mouse and human neurons and astroglia in vitro. Aim 2 will determine whether about opiates and gp120/Tat virotoxins, which both destabilize intracellular Ca2+ and increase reactive oxygen species, act through similar pathways by blocking putative toxic signaling events. Aim 3 will identify morphine-induced alterations in toxicity in striatal neurons and glia in vivo in mice stereotaxically injected with gp1201Tat viral proteins. Our goal is to determine the mechanisms by which opioids contribute to the pathobiology of HIV infection in the central nervous system, and to identify the underlying signaling pathways that could be targeted for therapeutic intervention.